Scientific Discoveries Supporting Theories in Science: From Thinking to Practice

Dear Colleagues,

Financial Times, in 2008, published an apparently provocative article with the title “Drug research needs serendipity” (1). In this visionary article, the authors state that, in the last two decades, the Pharma industry did not introduce new drugs to the market that showed some effectiveness against major diseases, despite huge investment, and they tried to propose some explanation for this. In their own words: “What went wrong? The answer, we suggest, is the mis-measure of uncertainty, as academic researchers underestimated the fragility of their scientific knowledge, while pharmaceuticals executives overestimated their ability to domesticate scientific research.’’ and ‘‘Medical research is particularly hampered by the scarcity of good animal models for most human disease, as well as by the tendency of academic science to focus on the ‘‘bits and pieces’’ of life – DNA, proteins, cultured cells – rather than on the integrative analysis of entire organisms, which can be more difficult to study.’’ All readers of these few sentences should realize that pharmaceutical industries have failed in their investment, and the authors of the article provide an explanation for this: academic researchers have overestimated their findings and the headquarters of Pharma were unable to achieve perfect control over what came from the scientific research. One paradox of this low effectiveness of the new drugs is that a new field in pharmacology is dedicated to discovering the off-targeting of known drugs through their side effects, (2) and this is leading to further thought regarding using drugs thought to be specific to a particular disease for the treatment of other diseases. However, this is not surprising as the vast majority of drugs that pioneered the pharmacology of neurologic diseases have been considered for other uses (3). From this dreadful awareness, some doubts may surface regarding the future of current research, that is, concerns about proceeding without breaks in the same direction. However, the authors provide a possible attempt to adjust this, to course-correct, to change the strategy of research in medicine in order to obtain results that may really change the health, and therefore the fate, of humanity. They wrote that, in the past, the majority of discoveries were mostly done through serendipity. In fact, serendipity was a fairly common occurrence in science.

We have clear examples of past discoveries that really changed history regarding devastating diseases, such as infectious diseases, through incidental findings, and, therefore, we can recall amazing moments of serendipity. The most known example of this is the discovery of penicillin. Fleming was studying ‘‘Staphylococcus influenzae’’ when one of his culture plates became contaminated and developed a mold that created a bacteria-free circle. Then, he found within the mold a substance that was very active against the vast majority of the bacteria infecting human beings (4). However, although Fleming’s example is the most known, it is not the only one we can provide. One other example, while much less known, is that of the 1931 Nobel Prizewinner Otto H. Warburg. He left some plates containing tumor cells seeded in culture medium in the laboratory’s incubator overnight with the usual 37°C and O₂/CO₂ atmosphere. The morning after, he realized that the O₂ dropped down within the incubator, expecting to find all the cells dead due to the hypoxic conditions. However, the cells were pretty well and, after his initial astonishment, he thought that cancer cells likely did not need oxygen to live. After a series of experiments, his conclusion was that, differently to normal cells, cancer cells do not need oxygen for their metabolism, while they ferment sugar-producing lactate, thus contributing to extracellular acidification. Warburg has become a mentor for scientists who think that tumor acidity is a common phenotype of cancers, and antiacidic therapy should be listed for implementation alongside the current anti-cancer approach. Warburg’s discovery on tumor metabolism convinced me that it is crucial, in science, to have a look to what is occurring with an open mind, not thinking that what looks like failure of your experiment is actually a failure, but instead, hopefully, something that may represent a discovery (5, 6). Therefore, we should identify serendipity as part of the scientific process, suggesting that ‘‘unexpected discoveries’’, should become part of life science. Serendipity should likely be considered an essential part of the scientific method and, particularly, a tool for progress, and it should be taken as a rational approach to scientific practice, an attitude, and a happy accident. We should not think of serendipity as merely luck, chance, or happenstance, but instead as a process in which a fortunate event leads to the discovery of a new, unexpected solution to a problem (7).

This Special Issue, hosted and proposed by the International Journal of Molecular Science, would like to collect reviews and original articles that relate to the topics I have discussed.

Original articles should represent a solid background boosting and feeding new theories on disease pathogenesis. Some examples are given in the following:

1. Logozzi M, Angelini DF, Giuliani A, Mizzoni D, Di Raimo R, Maggi M, Gentilucci A, Marzio V, Salciccia S, Borsellino G, Battistini L, Sciarra A, Fais S. Increased Plasmatic Levels of PSA-Expressing Exosomes Distinguish Prostate Cancer Patients from Benign Prostatic Hyperplasia: A Prospective Study. Cancers (Basel). 2019 Sep 27;11(10). pii: E1449. doi: 10.3390/cancers11101449.

THIS PAPER SUGGESTS THAT PLASMATIC EXOSOMES EXPRESSING TUMOR BIOMARKERS, SUCH AS PSA, MAY WELL REPRESENT REAL TUMOR BIOMARKERS

2. Logozzi M, Angelini DF, Mizzoni D, Di Raimo R, Battistini L, Fais S. Nanovesicles released by OKT3 hybridoma express fully active antibodies.Enzyme Inhib Med Chem. 2021 Dec;36(1):175-182. doi: 10.1080/14756366.2020.1852401.

THIS PAPER SUGGESTS THAT THE MOST EFFICIENT AND NATURAL WAY TO PRODUCE THERAPEUTIC ANTIBODIES MAY BE ON EXOSOMES.

The reviews should contain theories based on recent scientific data. Some examples might be:

1. Cappello F, Logozzi M, Campanella C, Bavisotto CC, Marcilla A, Properzi F, Fais S. EXOSOME LEVELS IN HUMAN BODY FLUIDS: A TUMOR MARKER BY THEMSELVES? Eur J Pharm Sci. 2017 Feb 15;98:64-69. doi: 10.1016/j.ejps.2016.11.007. PMID:27840195.
   THE THEORY PRESENTED HERE IS THAT THE PLASMATIC EXOSOMES LEVELS MAY REPRESENT A REAL DISEASE MARKER, AS THEY ARE ALWAYS HIGHER IN PATIENTS THAN IN HEALTHY DONORS.
2. Spugnini E, Fais S. Proton pump inhibition and cancer therapeutics: A specific tumor targeting or it is a phenomenon secondary to a systemic buffering? Semin Cancer Biol. 2017 Jan 11. pii: S1044-579X(17)30003-2. doi: 10.1016/j.semcancer.2017.01.003.
   THE THEORY PRESNTED HERE IS THAT PROTON PUMP INHIBITORS, WHILE HAVING A SPECIFIC CELLULAR TARGET, MAY CONTRIBUTE TO BODY ALKALINIZATION BY BUFFERING THE STOMACH.
3. Fais S, Overholtzer M. Cell-in-cell phenomena in cancer. Nature Reviews in Cancer. 2018 2018 Dec;18(12):758-766.
   THE THEORY PRESENTED IN HERE IS THAT CELL-IN-CELL PHENOME MAY REPRESENT A KEY CANCER PHENOTYPE AND A TUMOR MARKER.

 All the scientific papers and reviews that are related to the above examples will be welcome in this Special Issue.

References

1. Shaywitz D, Taleb N. Drug research needs serendipity. Financial Times; July 30, 2008.
2. Campillos M, Kuhn M, Gavin AC, et al. Drug target identification using side-effect similarity. Science 2008;321:263–6.
3. Ban TA. The role of serendipity in drug discovery. Dialog Clin Neurosci 2006;8:335–44.
4. Gaynes, R. The Discovery of Penicillin—New Insights After More Than 75 Years of Clinical Use. Emerg Infect Dis 2017, 23, 849–853.
5. Otto, A.M. Warburg effect(s)—a biographical sketch of Otto Warburg and his impacts on tumor metabolism. Cancer Metab 2016, 4.
6. Schwartz L, Seyfried T, Alfarouk KO, Da Veiga Moreira J, Fais S. Out of Warburg effect: An effective cancer treatment targeting the tumor specific metabolism and dysregulated pH. Semin Cancer Biol. 2017 Jan 22. pii: S1044-579X(17)30005-6. doi: 10.1016/j.semcancer.2017.01.005. PMID:28122260.
7. Foletti A, Fais S. Unexpected Discoveries Should Be Reconsidered in Science-A Look to the Past? Int J Mol Sci. 2019 Aug 15;20(16). pii: E3973. doi: 10.3390/ijms20163973.

Prof. Dr. Stefano Fais
Guest Editor

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